Calcium channel modulation by CaBP1 during aging

海马电压门控性钙通道（VGCC）内钙内流的改变显著影响海马突触的可塑性，这可能是老年人认知功能下降和记忆丧失的重要原因。VGCC受多种细胞因子调节，其表达可随衰老而改变。L型和P/Q型VGCC都受Ca 2+传感器钙调蛋白（CAM）的调节，CAM与这些通道的主要成孔α 1亚基结合。此外，CaBP 1，一种与CaM相关的蛋白质，与P/Q型通道的CaM结合结构域相互作用，但引起这些通道的强烈的、Ca 2+非依赖性抑制，这与CaM对其的调节令人惊讶地不同。以往的研究表明，与CaBP 1相关的Ca 2+结合蛋白随着年龄的增长而下调。CaBP 1和VGCC的细胞和亚细胞定位在海马中惊人地相似，其中突触可塑性长期以来一直与学习和记忆的控制有关。因此，CaBP 1对VGCCs的调节可能会严重影响神经元Ca 2+信号和神经功能在衰老大脑中的调节和潜在失调。该建议的具体目标是：（1）表征CaBP 1和VGCC之间的功能相互作用;（2）确定海马中CaBP 1相对于VGCC的细胞和亚细胞定位;以及（3）确定CaBP 1和VGCC之间的相互作用是否在衰老大脑中改变。实现这些目标将加强目前对正常和老年动物神经元VGCC功能的理解。此外，拟议的研究将允许未来分析VGCC调制中年龄相关变化的神经生理学后果，这可能揭示替代药理学策略，以抵消正常衰老和神经病理学状况（如阿尔茨海默病）导致的认知缺陷。

Age-related alterations in Ca 2+ influx through voltage-gated Ca 2+ channels (VGCCs) significantly affect synaptic plasticity in the hippocampus, which may contribute to the cognitive decline and memory loss in elderly humans. VGCCs are modulated by various cellular factors, the expression of which may change with aging. Both L- and P/Q-type VGCCs are regulated by the Ca2+-sensor calmodulin (CAM), which binds to the main pore-forming alpha1 subunit of these channels. In addition, CaBP 1, a protein related to CaM, interacts with the CaM-binding domain of P/Q-type channels but causes a strong, Ca2+-independent inhibition of these channels that is surprisingly different from their modulation by CaM. Previous studies indicate that Ca2+-binding proteins related to CaBP1 are down-regulated with age. The cellular and subcellular localization of CaBP 1 and VGCCs is strikingly similar in the hippocampus, where synaptic plasticity has long been implicated in the control of learning and memory. Therefore, the modulation of VGCCs by CaBP1 may critically influence how neuronal Ca 2+ signals and neurological functions are regulated and potentially dysregulated in the aging brain. The specific aims of this proposal are to: (1) characterize the functional interactions between CaBP1 and VGCCs; (2) define the cellular and subcellular localization of CaBP 1 with respect to VGCCs in the hippocampus ; and (3) determine if interactions between CaBP 1 and VGCCs are altered in the aging brain. Accomplishing these objectives will strengthen current understanding of the function of neuronal VGCCs in both normal and aged animals. In addition, the proposed research will permit future analyses of the neurophysiological consequences of age-related changes in VGCC modulation, which may reveal alternative pharmacological strategies to offset cognitive deficits resulting from normal aging and neuropathological conditions such as Alzheimer's disease.